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Oncology Board Review Manual
Statement of
Editorial Purpose
The Hospital Physician Oncology Board Review
Manual is a study guide for fellows and practicing
physicians preparing for board examinations in
oncology. Each manual reviews a topic essential
to the current practice of oncology.
PUBLISHING STAFF
PRESIDENT, Group PUBLISHER
Bruce M. White
Senior EDITOR
Robert Litchkofski
executive vice president
Barbara T. White
executive director
of operations
Jean M. Gaul
Epithelial Ovarian Cancer:
Evaluation, Staging, Surgery,
and Stage I and II Disease
Management
Editor:
Arthur T. Skarin, MD, FACP, FCCP
Distinguished Physician, Dana-Farber Cancer Institute,
Harvard Medical School, Boston, MA
Contributors:
Suzanne Berlin, DO, MHE
Dana Farber Cancer Institute, Susan F. Smith Center for
Women’s Cancer, Gynecologic Oncology Program, and
Harvard Medical School, Boston, MA
Joyce F. Liu, MD, MPH
Dana Farber Cancer Institute, Susan F. Smith Center for
Women’s Cancer, Gynecologic Oncology Program, and
Harvard Medical School, Boston, MA
Table of Contents
NOTE FROM THE PUBLISHER:
This publication has been developed with­
out involvement of or review by the Amer­
ican Board of Internal Medicine.
Hospital Physician Board Review Manual
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Epidemiology and Risk Factors . . . . . . . . . . . . . . 1
Clinical Evaluation and Initial Management. . . . . 2
Staging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Management of Stage I and II Stage Disease. . . . 7
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Board Review Questions. . . . . . . . . . . . . . . . . . . 13
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
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Epithelial Ovarian Cancer
Oncology Board Review Manual
Epithelial Ovarian Cancer: Evaluation, Staging, Surgery,
and Stage I and II Disease Management
Suzanne Berlin, DO, MHE, and Joyce F. Liu, MD, MPH
INTRODUCTION
Ovarian cancer is the second most common
gynecologic cancer among women in the United
States. It is also the fifth leading cause of cancer
mortality in women and the leading cause of death
among women with gynecologic malignancies.
The American Cancer Society statistics released
in 2015 estimate that 21,290 new cases of ovarian cancer will occur during the year, with approximately 14,180 deaths.1 Globally, there were
238,719 new cases of ovarian cancer diagnosed in
2012, representing 3.6% of all cancers in women,
and nearly 151,905 deaths.2 The highest incidence
of ovarian cancer occurs in northern, central, and
eastern Europe, followed by western Europe and
North America, with the lowest incidence in parts
of Africa and Asia. The majority of women presenting with ovarian cancer will present at an advanced
stage, and the 5-year survival in this group is less
than 30%.3
In this review, the first of 2 articles on ovarian
cancer, the clinical case will guide the discussion
of presenting symptoms and workup of ovarian
cancer and the management of stage I and stage II
disease, based on the literature and present standard of care. The second article will be published
in the Oncology Board Review Manual, Volume 11,
Part 3, and focus on the management of advanced
stage ovarian cancer.
Epidemiology and Risk Factors
Epithelial ovarian cancer was originally thought
to derive from malignant transformation of the
ovarian surface. However, in studying patients with
the high-grade serous subtype, recent reports
have now postulated that the origin may be the
fallopian tube,4,5 and molecular evidence has been
reported in a developed mouse model.6
The average lifetime risk of developing ovarian
cancer in the U.S. general population is 1.4% to
1.8%, and multiple risk factors can predispose a
woman to developing the disease.7,8 These risks
include age, with a median age at diagnosis of 60
years, early menarche, and late menopause, as
well as nulliparity,9–12 which has been hypothesized
to be related to increased trauma and repair to
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inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment.
www.turner-white.comOncology Volume 11, Part 2 1
Epithelial Ovarian Cancer
the ovarian epithelium due to uninterrupted cycles
of ovulation. Also, using estrogen alone for more
than 10 years in the postmenopausal setting as
hormone replacement therapy increases the risk
of ovarian cancer; this risk was reported to persist
for up to 29 years after estrogen was stopped.13
Talc in talcum powder used on the perineum or on
sanitary napkins may be associated with increased
risk of ovarian cancer.14
In contrast, the use of oral contraceptives,15,16 an
increased number of pregnancies,17 and breastfeeding18 have been shown to reduce ovarian
cancer risk. Tubal ligation has also been correlated
with a reduced risk of ovarian cancer, although the
mechanism is unknown.19 Also, although additional
studies are recommended, the recent reports on
treatment of infertility and risk for ovarian cancer
do not substantiate a correlation.20,21 The risks for
developing ovarian cancer were evaluated in a
case-control study in Sweden, which supported
the findings noted in previous studies, showing no
correlation between treatment for infertility and the
development of ovarian cancer.22
Ovarian carcinomas are now divided into 5 main
groups based on histopathology and genetics:
high-grade serous, endometrioid, clear cell, mucinous, and low-grade serous types. In addition,
histologic subtype can also determine prognosis.23
Family history is an important risk factor for
developing ovarian cancer. Women with 1 affected relative have a 5% estimated lifetime risk
of developing ovarian cancer, while women with 2
affected relatives have an estimated risk of 7% (in
contrast to an estimated risk in the general population of 1.6%).24 In the hereditary ovarian cancer
syndromes, the lifetime risk of developing ovarian
cancer ranges from 25% to 50%. Overall, hereditary ovarian cancer syndromes may account for
up to 10% to 15% of all ovarian cancer cases.25
2 Hospital Physician Board Review Manual
Genetic testing of patients with ovarian carcinoma
should be in accordance with the recently updated
National Comprehensive Cancer Network (NCCN)
guidelines (version 1.2015).26
Hereditary ovarian cancer syndrome presently
includes the 2 BRCA genes, BRCA1 and BRCA2.
Women carrying a BRCA1 germ-line mutation
have been estimated to have a lifetime risk of ovarian cancer ranging from 16% to 62%,27,28 while the
lifetime risk of ovarian cancer for women with a
BRCA2 germ-line mutation has been estimated to
be 10% to 15%.29,30
Studies have suggested that ovarian cancers
occurring in BRCA mutation carriers have a better
prognosis compared to cancers occurring in the
general population.22,31–33 Histopathology is typically high-grade serous for the BRCA group; there is
an association reported between BRCA2 and clear
cell histopathology, but research is still ongoing.34
Another familial syndrome associated with ovarian cancer is the Lynch syndrome, which is associated with mutations in the DNA mismatch repair
genes MSH2 and MLH1. Carriers of these germline mutations are most likely to develop colorectal
cancer or endometrial cancer, but also have an
elevated risk for ovarian cancer, with an estimated
lifetime risk of 9%.35 Also, there are less common
mutations in genes, such as RAD51D, which can
predispose women to a 1 in 11 chance of developing ovarian cancer.36
CLINICAL EVALUATION AND INITIAL
MANAGEMENT
CASE PATIENT
Initial Presentation and Evaluation
A 45-year-old G0 woman who has experienced
a several-month history of irregular periods followed by the presence of discomfort in the left
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Epithelial Ovarian Cancer
lower quadrant presents several months after the
start of her symptoms to her primary care physician, who considers the diagnosis of diverticulitis.
She undergoes a computed tomography (CT)
evaluation, which shows no active diverticular disease, but the left adnexal area is difficult to define.
She follows up with her gynecologist, who orders
a transvaginal ultrasound (TVUS). This reveals a
septated and cystic left ovary measuring 10.5 ×
6.0 cm. The right ovary is normal in appearance
and size.
• What are the signs and symptoms of epithelial ovarian cancer?
CLINICAL FEATURES
The symptoms of ovarian cancer may be subtle
or intermittent and mimic gastrointestinal issues
such as gastroesophageal reflux disease (GERD)
or a change in routine bowel habits. Given this presentation, patients may be initially referred to the
gastroenterologist for evaluation, including endoscopy workup. Symptoms can also include vague
abdominal discomfort, bloating, early satiety, constipation, indigestion, fatigue, urinary pressure/
incontinence, and rarely, vaginal bleeding.37–39
A retrospective survey suggests that these symptoms may occur in the majority of patients prior
to their diagnosis,40 but early diagnosis remains
difficult due to their nonspecific nature. It is possible but unusual for patients to present with acute
symptoms due to ovarian tumor rupture or torsion.
Less commonly, ovarian cancer can also be associated with several paraneoplastic syndromes.
The sign of Leser-Trélat, a rare phenomenon characterized by a sudden eruption of pruritic seborrheic keratoses, has been reported with ovarian
cancer.41 Symptoms of paraneoplastic syndromes
may precede the diagnosis. These entities can
include humoral-mediated hypercalcemia of malignancy (associated with clear cell carcinomas
of the ovary),42 as well as subacute cerebellar
degeneration.43 Trousseau syndrome, a superficial
migratory thrombophlebitis, has also been associated with ovarian cancer resulting in thrombosis.44
A general review of rheumatologic disorders and
associated paraneoplastic features involving ovary
is discussed by Racanelli and colleagues.45
• What diagnostic studies should be performed for patients with suspected ovarian
cancer?
DIAGNOSTIC WORKUP
The workup for a woman suspected of having ovarian cancer should include a full physical
examination to assess for adnexal mass, pleural
effusion, and ascites. TVUS provides an initial
evaluation of the pelvis. Features which can be
found on the ultrasound and are associated with a
malignant ovary include the presence of a complex
ovarian cyst with either solid and/or cystic components, septations, ascites, peritoneal masses,
or enlarged lymph nodes.46 However, in primary
peritoneal carcinoma, which is treated the same as
ovarian carcinoma, a mass will not be present, but
other features such as abdominal pain, effusions,
ascites, and adenopathy will be noted.47
A full staging CT exam is appropriate to confirm
the extent of disease present. Also, labs including
complete blood count (CBC) with differential, comprehensive chemistry, and tumor markers such
as CA-125, carcinoembryonic antigen (CEA), and
CA19-9 (if gastrointestinal primary is considered)
can be ordered. CT findings can demonstrate a
thickened omentum (cake), ascites, pelvic or adnexal mass, or hydronephrosis. The CA-125 level
can either be elevated or within the normal range,
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Epithelial Ovarian Cancer
but using the combination of CA-125 and CEA can
differentiate between ovarian and non-ovarian malignancy.48
When working up typical findings of ascites or
pelvic mass, other possible malignancies should
be considered, including those which can metastasize to the ovary, as well as other primary malignancies. Signet-ring cell neoplasms, which originate
from primary gastric carcinomas and metastasize
to the ovaries bilaterally, can form Krukenberg tumors. Other primary sites that can metastasize to
the ovary include upper and lower gastrointestinal
tract cancers,49 breast cancer50 as well as primary
lymphomas, which can present with adenopathy.51
CASE CONTINUED
Staging CT including the chest does not show
evidence of distant metastatic disease. Her family
history is without malignancy per her report. The
CA-125 is elevated at 370 U/mL.
• What is the significance of the CA-125 level?
CA-125 levels are elevated in approximately 80%
of postmenopausal women with advanced disease, but an elevated level is not always diagnostic of disease.52–54 CA-125 levels can be elevated
with any disease or inflammation affecting the
pleural or peritoneal lining. This can include other
malignancies such as breast and lung cancer as
well as benign conditions such as endometriosis,
uterine leiomyoma, and pelvic inflammatory disease, inflammatory diseases, and physiological
conditions.55 CA-125 levels are known to fluctuate with the menstrual cycle. The marker can
also be elevated in women with cirrhosis.56 The
use of CA-125 as a screening test is limited by its
poor sensitivity in early-stage disease, with CA125 levels elevated in only 50% of patients with
4 Hospital Physician Board Review Manual
stage I disease. Additionally, approximately 1% of
healthy women have a minimally elevated CA-125
level.57
A human epididymis protein 4 (HE4) assay was
approved by the U.S. Food and Drug Administration (FDA) in 2011 for use with the CA-125 as a
quantitative test developed to aid the gynecologic
surgeon. The Risk of Ovarian Malignancy Algorithm (ROMA), which derives a numerical score
from the results of the CA-125 and HE4 blood
tests, as well as menopausal status, defines which
patients with newly found adnexal masses will
be considered high risk and found to have malignancy. Results of this study showed a sensitivity of
88.4% and a specificity of 67.2% in both pre- and
postmenopausal women.58
•
Are there effective screening methods in detecting ovarian cancer?
SCREENING
Screening for ovarian cancer is not currently recommended for the general population but may be
appropriate for those considered at high risk (those
with a strong family history of ovarian, breast,
colon, or prostate malignancy or with known BRCA
mutations). When evaluating women who have
been diagnosed with ovarian cancer, they should
be screened for BRCA mutation as per the NCCN
guidelines (version 2.2014).59
Several clinical trials have attempted to validate
a screening program. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is
a large population-based randomized study sponsored by the National Cancer Institute (NCI). It has
collected data on the effects of cancer screening
in men and women aged 55 to 74 years. However,
in the ovarian group, the use of TVUS and CA-125
did not reduce ovarian cancer mortality.60
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Epithelial Ovarian Cancer
The UK Collaborative Trial of Ovarian Cancer
Screening (UKCTOCS) is a prospective, randomized
trial which has accrued more than 200,000 postmenopausal women aged 50 to 74 years.61 The
study began recruiting women in 2001 in the UK.
These women were then randomized to 3 arms:
control arm with no screening, annual screening with
TVUS, or annual CA-125 screening interpreted using
a risk of ovarian cancer algorithm which adds serial
measurements of CA-125 with TVUS as a secondline test. The endpoint of the study is to show an effect on mortality. The accrual was completed in 2005
showing that a screening program could be possible
using these tests, and the women are being followed
until 2015.61 The most recent publication evaluated
the psychological morbidity associated with ovarian
cancer screening.62
Other screening modalities include the Risk of
Ovarian Cancer Algorithm (ROCA). This strategy
utilizes a mathematical model based on the patient’s age and CA-125 score calculated over time,
and patients are stratified into 1 of 3 risk groups,
with the high-risk group referred for TVUS and to
a gynecologic surgeon. Of the 10 women who had
surgery based on TVUS, 4 invasive cancers were
found, stages IA to IIB. The specificity was 99.9%.
The authors concluded that ROCA followed by
TVUS had excellent specificity for the average-risk
population of women.63
• What is the next appropriate step in the evaluation and initial management of a patient
with suspected ovarian cancer?
SURGICAL MANAGEMENT
General Surgical Concepts
Cytoreductive surgery has played an important
role in the management of advanced ovarian cancer since Griffiths demonstrated in 1975 that an in-
verse relationship existed between overall survival
and residual tumor size.64 This has been confirmed
in subsequent studies, and a meta-analysis of 81
cohorts of patients with stage III or IV disease
from clinical trials conducted between 1989 and
1998 suggested that for every 10% increase in the
proportion of patients achieving maximal cytoreduction (defined in this meta-analysis as residual
disease ≤3 cm in maximal dimension), there was
an approximate 5.5% improvement in length of
overall survival.65
The exact degree of debulking required to classify a cytoreductive procedure as “optimal” has undergone revision. Currently, the accepted Surgical
Gynecologic Oncology Group definition states that
optimal cytoreduction has been achieved if there is
no gross residual.66 Primary cytoreductive surgery
is the present standard procedure in management
of ovarian disease, with studies noting that maximal cytoreduction remains the basis for successful
management of ovarian cancer.67
For women with suspected ovarian cancer
based upon radiologic imaging, physical examination, and laboratory data, surgical consultation
with a gynecologic oncologist is the next step
in the evaluation since it has been reported that
patients are more likely to receive an optimal
cytoreductive procedure when the operation is
performed by a gynecologic oncologist.68,69 If indicated, the gynecologic oncologist will perform a
cytoreductive procedure including total abdominal
hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), omentectomy, and careful examination of all bowel and organ surfaces. Biopsy
samples are taken from the peritoneal surfaces,
including the diaphragm, and sampling of the
para-aortic and pelvic lymph nodes can be performed. Any peritoneal fluid is sent for cytologic
evaluation.
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Epithelial Ovarian Cancer
Surgery in Advanced Disease
The concept of optimal cytoreduction in advanced disease has been reviewed by Markman,70
with the conclusion that the benefits of primary
surgical cytoreduction in advanced stage patients
need to be supported by clinical trial data. There
was good evidence that the size of the postoperative residual tumor was prognostic and is the topic
of several phase 3 studies.
Several prospective studies put forth by the
AGO-OVAR and GINECO looked at the role of
surgical outcome as the prognostic factor in advanced disease. There were 3126 patients evaluated within each of 3 groups: complete resection,
small residual (1 to10 mm), or residual exceeding
1 cm.71 The multivariate analysis demonstrated improved progression-free survival (PFS) and overall
survival (OS) for those women who achieved complete resection compared with the other 2 groups
(P < 0.0001). Additional independent prognostic
factors included age, performance status, grade,
stage, and histology. The conclusion was that the
goal of primary surgery should be complete resection.71 However, patients with findings which could
exclude successful surgery such as large-volume
disease which is unresectable, or lung, mediastinal, or pleural involvement may benefit from a
neoadjuvant approach.
The results from the EORTC-NCIC randomized study EORTC55971 suggested neoadjuvant
chemotherapy (NACT) could be an alternative to
the standard treatment approach in this subgroup
of women with advanced disease.72 The results
from this study demonstrated that NACT followed
by interval cytoreductive surgery was not inferior
to primary surgery followed by chemotherapy for
patients with stage IIIC or IV disease. In this study,
670 patients with biopsy-proven invasive epithelial
ovarian carcinoma, primary peritoneal carcinoma,
6 Hospital Physician Board Review Manual
or fallopian-tube carcinoma were randomized to either receive primary cytoreductive surgery followed
by adjuvant chemotherapy or NACT followed by
interval cytoreductive surgery and then additional
platinum-based chemotherapy. Complete resection of all macroscopic disease (1 cm or less) was
the strongest independent variable for predicting
OS in both groups. The median OS in the group
receiving primary surgery was 29 months and in
the initial NACT group, 30 months. The hazard
ratio (HR) for death in the NACT/surgery group
compared with the surgery/chemotherapy group
was 0.98 (P = 0.01 for noninferiority). The author
concluded that NACT/surgery resulted in the same
survival but with fewer complications than performing primary cytoreductive surgery on this group.72
The MRC CHORUS trial (CRUK 07/009) is the
other randomized phase 3 trial evaluating when
to perform surgery in advanced ovarian cancer
patients.73 The group included stage III-IV patients
who were randomized to either standard treatment
(primary surgery followed by 6 cycles of chemotherapy) or NACT (3 cycles of chemotherapy followed by cytoreductive surgery then completion
chemotherapy). This trial was also designed as
a noninferiority study. Primary outcome was OS
and secondary outcome was PFS. A total of 550
women were randomized into the 2 well-balanced
groups. The median OS was 22.8 months for the
primary surgery group and 24.5 months for the
NACT group, with the HR of 0.87 favoring the NACT
group. The PFS was 10.2 months in the primary
surgery group and 11.7 months in the NACT group.
The conclusion was that NACT allowed for increased optimal cytoreduction, less early mortality,
and similar survival. These results are consistent
with the results found in the EORTC55971 trial
regarding the role of NACT as an alternative in this
group of woman with advanced disease.73
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Epithelial Ovarian Cancer
Experience from Memorial Sloane Kettering
Cancer Center using the same patient criteria
showed that only 10% of these patients received
NACT, with optimal cytoreduction (<1 cm) achieved
in 71% of the patients. The PFS was 17 months,
while the OS was 50 months. The conclusion was
that primary cytoreductive surgery should remain
the standard of care for the majority of women with
advanced ovarian carcinoma, as reported at the
9th International Conference on Ovarian Cancer.74
be dissected away, and it is removed intact. The
final pathology report indicates the left ovary to be
malignant, grade 2, endometrioid type with rupture
and surface involvement, and the fluid is negative
for malignancy as were the fallopian tubes, uterus,
bilateral pelvic nodes sampled, and omentum. Her
stage is IC2.
STAGING
Treatment decisions are based on stage of disease, and the NCCN guidelines serve to outline
management decisions. The NCCN was initially
formed in 1995 with 13 academic cancer institutions. The goals included providing clinical practice guidelines to establish uniform quality cancer
care. There are now 23 member institutions across
the United States whose board members actively
update the guidelines based on scientific developments.26
Stage is an important factor in determining prognosis and treatment for ovarian carcinoma. Based
upon the findings from surgery, staging is determined according to the American Joint Committee on
Cancer and International Federation of Gynecologic
Oncologists (FIGO) joint staging system (Table 1).
FIGO staging is used exclusively in gynecologic
malignancies, but one can correlate with the TMN
staging used for all other solid tumor types.
Case Continued
The patient is referred to a gynecologic surgeon
for consultation and, given the abnormality of the
left ovary, a standard cytoreductive surgery with
TAHBSO, omentectomy, diaphragm and gutter
biopsies as well as washings are recommended. At surgery, endometriosis is noted scattered
throughout the surgical field with adhesions, and
the left ovary is stuck to the pelvic sidewall. The
omentum is without disease upon visual inspection and the nodes are palpably normal. A small
amount of pelvic fluid is obtained for diagnostic
analysis. At the time of dissection of the left ovary,
there is evidence of rupture, but the ovary is able
to be removed in total. The right ovary is of normal size, the surrounding adhesions are able to
MANAGEMENT OF STAGE I AND STAGE II
DISEASE
• What are the treatment options for earlystage ovarian cancer?
EARLY-STAGE DISEASE
Early-stage (stage I disease) is associated with
a significantly better prognosis, with 5-year survival
ranging from approximately 65% to over 90%.75
In contrast, 5-year survival for stage III and stage
IV disease is estimated to be less than 40% and
less than 20%, respectively. However, even for
patients diagnosed with early-stage disease, there
is a significant risk of recurrence depending on
the histologic subtype, and these patients should
receive adjuvant chemotherapy following surgical
resection as noted in the NCCN guidelines.26
The NCCN guidelines define the treatments
based on grade and histologic type (Table 2).
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Epithelial Ovarian Cancer
Table 1. TNM and FIGO Staging Classifications for Ovarian Cancer
Primary tumor (T)
TNM
TX
T0
T1
T1a
FIGO
T1b
IB
T1c
IC
T2
T2a
II
IIA
T2b
T3
IIB
III
T3a
IIIA
T3b
IIIB
T3c
IIIC
I
IA
Primary tumor cannot be assessed
No evidence of primary tumor
Tumor confined to the ovaries (1 or both)
Tumor limited to 1 ovary; capsule intact, no tumor on ovarian surface; no malignant cells in ascites or peritoneal
washings
Tumor involves both ovaries; capsules intact, no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings
Tumor limited to 1 or both ovaries with any of the following:
IC1 – surgical spill
IC2 – capsule rupture before surgery or tumor on ovarian surface
IC3 – malignant cells in the ascites or peritoneal washings
Tumor involves 1 or both ovaries with pelvic extension (below the pelvic brim)
Extension and/or implant on the uterus and/or fallopian tube(s); no malignant cells in ascites or peritoneal
washings
Extension to other pelvic intraperitoneal tissues; no malignant cells in ascites or peritoneal washings
Tumor involves 1 or both ovaries with microscopically confirmed peritoneal metastasis outside the pelvis and/or
metastasis to the retroperitoneal lymph nodes
Positive retroperitoneal lymph nodes and/or microscopic peritoneal metastasis beyond the pelvis (no macroscopic tumor)
IIIA1 Positive retroperitoneal lymph nodes only
IIIA1 (i) Metastasis ≤10 mm
IIIA1 (ii) Metastasis >10 mm
IIIA2 Microscopic, extrapelvic (above the brim) peritoneal involvement ± positive retroperitoneal lymph nodes
Macroscopic, extrapelvic, peritoneal metastasis ≤2 cm in greatest dimension ± retroperitoneal lymph nodes.
Includes extension to capsule of liver/spleen
Macroscopic, extrapelvic, peritoneal metastasis >2 cm in greatest dimension ± positive retroperitoneal lymph
nodes. Includes extension to capsule of liver/spleen
(continued on page 9)
The subtypes of epithelial ovarian cancers are
endometrioid, serous, mucinous, and clear cell,
with Brenner’s and squamous types composing
less than 3%. Endometrioid is the most common
malignant subtype, followed by serous and then
mucinous and clear cell tumors (Table 3).76 These
subtypes as well as the low-grade serous tumors
may be distinct from high-grade serous carcinoma
and are classified as type I ovarian cancers. Type II
carcinoma comprises the high-grade serous group
(Table 4).77 Also, clear cell and mucinous tumors
8 Hospital Physician Board Review Manual
present more frequently at an earlier stage compared with serous tumors, and as an early stage
can have a better prognosis.78 Women presenting
with stage IC disease are treated with chemotherapy given the poor prognosis compared with stage
IA and IB disease, but it has been reported that if
the stage IC is due to intraoperative rupture, the
prognosis may be comparable to that of an earlier
stage.78 MD Anderson Cancer Center proposed a
2-tiered system for grading serous ovarian carcinoma that is based on the assessment of nuclear
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Epithelial Ovarian Cancer
Table 1. TNM and FIGO Staging Classifications for Ovarian Cancer (continued)
Regional lymph nodes (N)
TNM
NX
N0
N1
FIGO
IIIC
Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Regional lymph node metastasis
Distant metastasis (M)
TNM
M0
M1
FIGO
IV
No distant metastasis
Distant metastasis (excluding peritoneal metastasis)
IVA Pleural effusion with positive cytology
IVB Hepatic and/or splenic parenchymal metastasis, metastasis to extra-abdominal organs (including inguinal
lymph nodes and lymph nodes outside of the abdominal cavity)
Notes:
• The presence of nonmalignant ascites is not classified. The presence of ascites does not affect staging unless malignant cells are present.
• Liver capsule metastasis is T3/stage III; liver parenchymal metastasis, M1/stage IV. Pleural effusion must have positive cytology for M1/stage IV.
Other major recommendations for FIGO staging are as follows:
Histologic type including grading should be designated at staging.
Primary site (ovary, fallopian tube or peritoneum) should be designated where possible.
Tumors that may otherwise qualify for stage I but are involved with dense adhesions justify upgrading to stage II if tumor cells are histologically
proven to be present in the adhesions.
Adapted with permission from Ovary and primary peritoneal carcinoma. In: Edge SB, Byrd DR, Compton CC, et al, eds. AJCC cancer staging
manual. 7th ed. New York: Springer-Verlag; 2010:493–506; and Prat J; FIGO Committee on Gynecologic Oncology. Staging classification for cancer
of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 2014;124:15.
atypia with mitotic rate used as a secondary feature. The benefit would be to provide better reproducibility in the grading of serous ovarian tumors.80
Observation
Treatment for IA and IB, grade 1 is surgical staging followed by observation. This group is considered potentially curable with surgery alone, with
cure rates exceeding 90%.75 For patients with grade
2 stage IA or IB disease, observation may be a
consideration depending on the subtype as per the
NCCN guidelines.
Adjuvant Systemic Chemotherapy
For stage IA and IB, grade 2, adjuvant chemotherapy with a platinum and taxane doublet is
recommended following optimal cytoreduction. In
stage IA and IB, grade 3, stage IC or clear cell
type, adjuvant chemotherapy is recommended
after optimal surgical staging.
Early Gynecologic Oncology Group (GOG) trials validated the use of cisplatin-based chemotherapy.81 European groups also pursued this
research, including Gruppo Interregionale Cooperative Oncologico Gynecological (GICOG) which
compared cisplatin with a cisplatin-based regimen
in advanced ovarian cancer; their finding suggested that cisplatin by itself was as effective as a
platinum-based regimen.82
Two large, randomized prospective phase 3 trials have demonstrated a benefit of using platinumbased regimens for adjuvant chemotherapy, the
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Epithelial Ovarian Cancer
Table 2. NCCN Practice Guidelines Findings/Primary Treatment (NCCN 1.2015 OV-2)
Stage
Findings
Primary Treatment
Suspected stage IA or IB, grade 1
Suspected stage IA or IB, grade 2
–
If observation considered
Suspect residual disease
Suspect no residual disease
Suspected stage IA or IB, grade 3
or clear cell or stage IC
Suspect residual disease
Suspect no residual disease
Stage II, III, IV
Suspect potentially resectable residual disease
Surgical staging
Surgical staging
Completion surgery/surgical staging
Completion surgery/surgical staging or chemotherapy
for 6 cycles
Completion surgery/surgical staging
Completion surgery/surgical staging or chemotherapy
for 6 cycles
Tumor reductive surgery
Suspect unresectable residual disease
Chemotherapy for a total of 6–8 cycles
Consider completion surgery after 3 cycles followed by
postoperative chemotherapy
Adapted from NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer. Including fallopian tube cancer and primary peritoneal cancer.
Version 1.2015. http://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf. Accessed March 5, 2015.
International Collaborative Ovarian Neoplasm trial 1
(ICON1) and the Adjuvant Chemotherapy in Ovarian Neoplasm (ACTION) trial. These phase 3 trials
randomly assigned postsurgical patients to either
observation or platinum-based adjuvant chemotherapy. The ACTION trial enrolled 448 women with
high-risk, early-stage disease (FIGO stage IA-IB,
grade 2-3, all stage IC and IIA, and all stages I-IIA
with a clear cell component).83 Following cytoreductive surgery, patients were randomized to either
observation or treatment with between 4 and 6
cycles of platinum-based therapy. After a median
follow-up of 5.5 years, there was a statistically significant improvement in recurrence-free survival in
the arm receiving adjuvant treatment (HR = 0.063,
P = 0.02). ICON1 enrolled 477 early-stage patients,
regardless of tumor grade. Patients were treated
with 6 cycles of a platinum-based regimen.84 After a
median follow-up of 51 months, a statistically significant improvement in both OS (HR = 0.66, P = 0.03)
and recurrence-free survival (HR = 0.45, P = 0.03)
was observed. A combined analysis of these 2 in10 Hospital Physician Board Review Manual
ternational studies suggested a significant benefit
in 5-year OS in patients with higher-risk early-stage
disease who are treated with adjuvant therapy, 74%
versus 82% (P = 0.008), respectively.83
Of note, although recommended, complete staging surgery with TAH, BSO, and omentectomy were
not required for entry into the ICON1 trial, and taken
in conjunction, these data suggest a beneficial role
for the use of platinum-based adjuvant therapy, with
the ACTION trial demonstrating the greatest benefit
in those women who had suboptimal surgery, and
thus more advanced disease. The 10-year follow-up
in the ICON1 study has maintained significance for
recurrence-free survival (HR = 0.69; P = 0.02) and
overall survival (HR = 0.71; P = 0.04).85
Additional studies concerning adjuvant chemotherapy in early-stage disease have addressed the
question of how many cycles of platinum-based
therapy should be administered. GOG conducted
a randomized phase 3 trial (GOG 157) that enrolled 427 patients who received either 3 or 6
cycles of adjuvant carboplatin/paclitaxel.86 These
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Epithelial Ovarian Cancer
Table 3. Subtypes of Epithelial Ovarian Malignancies
Cancer Type
Malignant frequency (%)
Serous
36
Mucinous
5
Endometrioid
77
Clear Cell
3
Brenner’s
1
3 (Mixed)
Squamous
2 (Undifferentiated)
Adapted from Ozols RF, Rubin SC, Thomas GM, Robboy SJ. Epithelial ovarian cancer. In: Hoskins WJ, ed. Principles and practice of gynecologic
oncology. Philadelphia: Lippincott Williams & Wilkins; 2005:904.
results indicated a trend towards a lowered recurrence risk with 6 cycles of treatment (HR = 0.761,
P = 0.18). No difference in OS was observed. In
comparing 3 cycles versus 6 cycles, grade 3 or 4
neurotoxicity was significantly increased from 2%
to 11%, respectively, and there was more anemia
and granulocytopenia in those patients receiving 6 cycles. This study was updated in 2010 for
subgroup analysis, and a lower risk of recurrence
was noted in the serous group having 6 cycles
(HR = 0.33, P = 0.04). The findings also noted a
5-year recurrence-free survival advantage for 6
cycles (83%) versus 3 cycles (60%) in those with
serous tumors (P = 0.007).87
GOG 175 evaluated the recurrence-free interval (RFI) and safety profile in 542 patients with
fully resected high-risk early stage ovarian cancer
patients treated with intravenous carboplatin and
paclitaxel with or without maintenance low-dose
paclitaxel for 24 weeks.88 Patients with stage I-A/B
(grade 3 or clear cell), all IC, or stage II disease
were included. All patients received carboplatin
AUC 6 and paclitaxel 175 mg/m2 every 3 weeks
for 3 courses, with randomization to either observation or maintenance paclitaxel 40 mg/m2/week
for 24 weeks. Three cycles were completed by
97% and 80% of those assigned to maintenance
completed the regimen. Within the maintenance
group, peripheral neuropathy (15.5%), infection/
fever (19.9%), and skin reactions (70.8%) were
noted at grade 2 or worse. The probability of sur-
vival at 5 years was 85.4% for patients on maintenance paclitaxel and 86.2% for those patients in
surveillance. The conclusion was that maintenance
paclitaxel added to standard-dose carboplatin and
paclitaxel showed no significant increase in RFI.88
These studies of adjuvant chemotherapy in
early-stage disease are summarized in Table 5.
Adjuvant radiation therapy has also been investigated, but few randomized trials are available, and
its use as adjuvant therapy in ovarian cancer is not
commonly practiced.
STAGE II
For stage II disease following optimal cytoreduction to no gross residual, recommended treatment
is either standard chemotherapy with a taxane and
platinum agent given every 3 weeks or intraperitoneal chemotherapy.26
CASE PATIENT CONTINUED
The patient recuperates from surgery and, given
her stage which was defined by the capsular rupture, chemotherapy with paclitaxel and carboplatin
is recommended. The data on 3 versus 6 cycles of
treatment is reviewed with her, and since she is not
considered high risk by subtype (not pap serous or
clear cell type) but did have evidence of extensive
endometriosis, her physicians elect to treat for 6
cycles total. Her treatment course is unremarkable
since she is very compliant with prescribed antinausea medications, maintains good oral hydration
www.turner-white.comOncology Volume 11, Part 2 11
Epithelial Ovarian Cancer
Table 4. Summary of Subtype Characteristics
Characteristics
HGSC
LGSC
MC
EC
CCC
Risk factors
Precursor lesions
BRCA1/2
TIC
?
Atypical endometriosis
Very early
Transcoelomic
BRCA
P53
High
Poor
?
Cystadenoma/
borderline tumor
Usually confined
to ovary
KRAS
HER2
Low
Favorable
HNPCC
Atypical endometriosis
Patterns of spread
?
Serous borderline
tumor
Transcoelomic
Usually confined
to pelvis
PTEN
ARIDIA
High
Favorable
Usually confined
to pelvis
HNF1
ARIDIA
Low
Intermediate
Molecular abnormalities
Chemosensitivity
Prognosis
BRAF
KRAS
Intermediate
Intermediate
CCC = clear cell carcinoma; EC = endometrioid carcinoma; HGSC = high-grade serous carcinoma; LGSC = low-grade serous carcinoma;
MC = mucinous carcinoma; TIC = tubal intraepithelial carcinoma.
Adapted with permission from Prat J. New insights into ovarian cancer pathology. Ann Oncol 2012; 23(suppl 10):111–17.
and nutrition, and tries to keep an active lifestyle.
Her first CA-125 pre-cycle 1 was 100 U/mL and
after 3 cycles the marker drops to 20 U/mL. At the
completion of the course, the marker is 10 U/mL.
She has not experienced neuropathy and her CBC
was maintained throughout the course without the
need for growth factor support.
• Is there a role for maintenance chemotherapy?
There are no phase 3 studies defining maintenance chemotherapy as a treatment modality in
early-stage disease.
• How should the patient be monitored for disease recurrence?
Surveillance
For patients who achieve clinical response following adjuvant chemotherapy, surveillance is
typically conducted every 3 months and consists
of history and physical examinations (pelvic examination minimum of twice per year) and monitoring
CA-125 levels.
12 Hospital Physician Board Review Manual
An early study examining the correlation of CA125 levels with disease progression found the
CA-125 to be elevated in 73% of patients at the
time of progression, with elevation of CA-125 levels occurring before clinical progression in 63%
of all patients.89 In patients who had elevated
CA-125 levels before clinical progression, the
median lag time was 4.5 months (range 0.5–29.5
months).
The Gynaecologic Cancer Intergroup (GCIG)
has proposed a set of criteria, based upon the
CA-125 level in conjunction with standard RECIST
(Response Evaluation Criteria in Solid Tumors)
criteria, to evaluate clinical response and progression in clinical trials conducted by its participating
groups.90 Specifically, the GCIG/RECIST criteria
for disease response is a 50% reduction in CA-125
levels that is maintained for 28 days. The CGIG/
RECIST criteria for disease progression are dependent on the patient’s CA-125 level prior to treatment. For patients with an initially elevated CA-125
level that normalized following treatment or for patients who had a normal CA-125 level, progression
is defined as a CA-125 level 2 times greater than
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Epithelial Ovarian Cancer
Table 5. Studies of Adjuvant Chemotherapy in Early-Stage Epithelial Ovarian Cancer
Trial
Treatment
GOG 157
Bell et al 200686
Paclitaxel/carboplatin 3 vs 6 cycles
GOG 157
Chan et al 201087
GOG 175
Mannel et al 201188
Outcomes
5-yr DFS for 3 vs 6 cycles was 75% and 80%
5-yr OS for 3 vs 6 cycles was 81% and 83%
Subgroup analysis
5-yr DFS for 3 vs 6 cycles were 60% and 83%
(P = 0.007)
Hazard ratio for serous tumor having 6 cycles = 0.33
(P = 0.04)
Paclitaxel/carboplatin for 3 cycles in both arms, then 5-yr survival of 85.4% for maintenance paclitaxel vs
weekly paclitaxel for 24 wk vs observation
86.2% for observation
DFS = disease-free survival; OS = overall survival.
Adapted from Tangjitgamol S, Kavanagh, J. Cytotoxic trials by the Gynecologic Oncology Group. http://www.esgo.org/Education/PublishingImages/131.pdf. Accessed March 5, 2015.
the upper limit of normal on 2 occasions separated
by at least 1 week. For patients with initially elevated levels of CA-125 that did not normalize following
treatment, progression is defined as a CA-125 level
2 times greater than the nadir following treatment.
In patients with suspected recurrence, a CT scan
should also be considered to assess for the presence of visible disease. However, the sensitivity of
CT in some studies has been shown to be as low
as 40%, and the use of positron-emission tomography/CT has shown high sensitivity and positive
predictive value in diagnosing macroscopic recurrent disease in the setting of equivocal findings on
conventional CT.91
symptoms. She is then referred back to her local
gynecologist for long-term follow-up.
CONCLUSION
Based on early clinical trials, the benefit of surgery and chemotherapy has been established in
the management of ovarian carcinoma. In addition
to this standard, the issues of screening and maintenance are topics still undergoing study.
BOARD REVIEW QUESTIONS
Test your knowledge of this topic.
Go to www.turner-white.com and select Oncology
from the drop-down menu of specialties.
CASE PATIENT CONCLUSION
After completing chemotherapy, the patient begins the routine alternating schedule of follow-up between gynecologic surgery and medical oncology
every 3 months for 2 years and then every 6 months
for a total of 5 years, with the CA-125 checked at
each visit. She also sees a genetics specialist as
recommended by the NCCN guidelines, and BRCA
testing is negative for mutation. At the completion of
her 5 years of follow-up, her CA-125 remains at 22
U/mL and she is without gastrointestinal or pelvic
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